The origin of benign prostatic disease, such as benign prostatic hyperperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), is poorly understood. The public health burden of these conditions is considerable. Office visits in the US during which BPH is the primary diagnosis exceed 4.4 million yearly, with an associated annual health care cost of $1.1 billion. CP/CPPS, which can affect men of all ages, accounts for 3 million annual office visits, remains largely unexplored using modern molecular approaches, and is without effective therapy. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign disease and prostate cancer is still uncertain. Research into the mechanisms of lower urinary tract dysfunction in males may open new opportunities for therapy, however devising hypotheses involving signal transduction mechanisms targetable with pharmaceutical agents remains challenging because of the lack of information about the relevant biochemical pathways. Epidemiologic data suggest an association between BPH symptoms and cardiovascular disease (CVD). Population studies have also produced evidence that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while pre-clinical observations have shown that prostate cancer growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. These data suggest that cholesterol metabolism may play a role in the incidence or severity of lower urinary tract symptoms (LUTS) in men. Using a novel method of raising and lowering of circulating cholesterol in the mouse, our laboratory has provided new evidence that the normal prostate in situ. Prostatic epithelial cells in culture also sense and respond to changes in cholesterol levels in their microenvironment. Our data suggest that hypercholesterolemia may predispose to prostate pathology. In this application, we propose the first systematic analysis of the role of serum cholesterol variation in normal prostate physiology and benign pathology. We hypothesize that hypercholesterolemia can promote pathophysiologic changes that may increase the risk of BPH, CP/CPPS, or premalignant transformations associated with prostate cancer. We will challenge this hypothesis with the following specific aims: (1) Determine the physiologic consequences for the normal prostate of prolonged changes in levels of circulating cholesterol. (2) Determine whether a cholesterol-sensitive signaling network is activated in the prostate in response to prolonged changes in levels of circulating cholesterol, and identify critical nodes in this network. These studies will provide the first mechanistic information about the ability of the prostate to detect changes in circulating cholesterol, and because they employ an FDA-approved cholesterol-lowering compound (ezetimibe), the findings from this project may serve as the basis for prospective clinical trials. PUBLIC HEALTH RELEVANCE: Cholesterol, its metabolic derivatives, and the signaling pathways that are affected by cellular concentrations of this lipid, all play a significant role in cancer cell growth and survival, and are well established as mediators of inflammation in the cardiovascular system. We now have evidence that the normal prostate in situ, and prostate epithelial cells in culture, respond to changes in cholesterol in the microenvironment. In this proposal we present a plan for the first systematic analysis of the role of serum cholesterol in normal prostate physiology and benign pathology. Our experimental approach is hypothesis-driven, yet unbiased, and takes advantage of nearly 10 years of study in our lab of the role of cholesterol in signal transduction, systems-level expertise we have acquired in recent studies of benign prostatic disease, and advanced bioinformatics expertise of our collaborators. Our current data indicate that the prostate can sense sustained changes in circulating cholesterol and can mount a physiologic response. The experiments we have proposed will rigorously test this idea. Our primary goal is to determine the nature of this response and, in particular, whether hypercholesterolemia promotes pathophysiologic changes likely to increase the risk of: (1) benign prostatic hyperplasia, (2) chronic prostatitis/chronic pelvic pain syndrome and/or (3) prostate cancer.